This invention relates to a new class of chemical compounds having utility as antilittering agents. The novel compounds are diarylmethylenyl cyclohexane carbinols and esters thereof and are typified by compounds having the following molecular structure: ##SPC1##
Wherein R.sub.1 is hydrogen or --COR wherein R is lower alkyl of from 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and the like; R.sub.2 is hydrogen, a lower alkyl group of from 1-5 carbon atoms or a lower alkynyl group of from 2-5 carbon atoms such as ethynyl, propynyl, butynyl and the like; R.sub.3 and R.sub.4 are hydrogen, a lower alkyl group of from 1-5 carbon atoms, a lower alkoxy group of from 1-5 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like or a lower alkanoyloxy group of from 2-5 carbon atoms such as acetoxy, propionyloxy and the like. Preferred among the compounds represented above are those wherein R is lower alkyl and R.sub.3 and R.sub.4 are each hydrogen, although those compounds wherein R.sub.3 and R.sub.4 are lower alkoxy and lower alkanoyloxy also show good activity. The most preferred compound of the present invention is 1-(diphenylmethylenyl)-2-methyl-3-ethyl-4-acetoxycyclohexane.
The novel diarylmethylenyl cyclohexane carbinol esters and derivatives of the present invention can be prepared by reacting an appropriately substituted, protected cyclohexanone with a Grignard reagent carrying the desired aryl moiety of the final compound. Suitable protecting groups for the cyclohexanone include ketals such as the cyclic ethylene ketal and thioketals such as the cyclic ethylene thioketal. The resulting condensation product is then dehydrated, preferably in a strong acid catalyzing system, to effect formation of the methylene bridge. Suitable acid catalysts include p-toluenesulfonic acid, hydrochloric acid, sulfuric acid and the like. The acid-catalyzed reaction has no stereochemical affect on the alkyl groups. The ketone protecting group is then removed and the cyclohexanone compound which forms is a useful intermediate which also possesses some antilittering activity. The preferred reagent for regenerating the ketone from the protecting group is a mixture of mercuric chloride and cadmium carbonate. The cyclohexanone intermediate is then reduced to the hydroxy compound with an appropriate reducing agent such as a complex metal hydride. Suitable complex metal hydrides are lithium aluminum hydride, sodium borohydride and the like. The final step is an esterification process whereby the hydroxy group is converted to the appropriate ester function using standard esterification techniques.
The thioketals which are used as the starting materials in the preparation of the novel diarylmethylene cyclohexane carbinol esters are themselves novel compounds as are all of the compounds obtained during each step of the reaction sequence. The starting materials may be prepared in accordance with the procedures set forth in the Examples hereinafter presented.
It will be appreciated by those skilled in the art that stereochemical considerations may be encountered in the reaction sequence. It is an advantage of the present process, however, that the stereochemical relations of the groups are retained in the Grignard reactions and in the neutral process of regenerating the ketones from the thioketals. The compounds prepared by the above-described process have cis-methyl and cis-ethyl configurations relative to the ester moiety.
Alternatively the thioketal hydroxy compound may be first converted to an hydroxy cyclohexanone derivative as described above, followed by dehydration with strong acid. When this method is employed, however, some epimerization of the 3-ethyl group takes place.
As stated previously, the compounds of the present invention exhibit antilittering activity. In addition, the intermediates used in preparation of the novel diarylmethylenyl cyclohexane derivatives also exhibit antilittering activity in varying degrees.
The novel diarylmethylenyl cyclohexane derivatives of this invention differ in this regard from the closest prior art of which applicant is aware, namely U.S. Patent No. 3,287,397, dated November 22, 1966. In the above-noted patent, compounds having a bis-(alkoxyphenyl, benzyloxyphenyl and hydroxyphenyl) methylenyl cyclohexane moiety are disclosed together with some analogs thereof, wherein the cyclohexane moiety is alkyl substituted. This prior art, however, does not disclose compounds having the activity of the instant compounds nor does it disclose compounds wherein the cyclohexane moiety carries either the free carbinol or an esterified carbinol at the position para to the methylene bridge.
In the examples which appear hereinbelow, antilittering actitity is determined as follows:
A test group of rats is fed a calculated amount of a test substance in the feed for a period of 7 days during which time males and females are kept separate with both sexes receiving the test substance. Thereafter, the males and females are cohabited and the diet fed is continued for 15 days. At the end of this time, the cohabitation is ended and the drug removed from the diet. The females are then observed for a period of 21 days and are allowed to deliver their young, if any, and to raise them. A control group of rats is handled in precisely the same way at the same time except that their diet does not include the test substance.
As mentioned above, the compounds of the invention also exhibit post-coital antilittering effects when administered on days 9 through 12 after coitus in one single, oral dose per day. The effect is measured by determining the percent resorption of conceptuses at a particular dosage level. The novel compounds have been found to be effective when administered at dosage levels of from at least 0.5 mg/kg to about 25 mg/kg.